Insulin sensitisers and methods of treatment

Abstract

The present invention relates generally to the field of therapy. The invention particularly relates to insulin sensitizers and methods of regulating glucose homeostasis and to the therapeutic or prophylactic treatment of diseases and associated conditions, in which impaired glucose uptake due to insulin resistance is involved or implicated, such as diabetes, syndrome X, hyperglycaemia, vascular disease and kidney disease. The present invention further relates to compounds and agents and compositions thereof for use in the treatment methods.

We claim: 
     
       1. A method of lowering elevated or maintaining normal blood glucose levels in a subject in need thereof, consisting essentially of administering to said subject an effective amount of a compound of Formula (III) as a sole anti-diabetic or anti-hyperglycemic agent, 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from hydrogen, C 1-6 alkyl, C(O)C 1-6 alkyl and (CH 2 ) n  phenyl, where n is 1, 2, 3, 4, 5 or 6 and phenyl may be unsubstituted or optionally substituted by one or more substituents independently selected from C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, nitro, OC(O)C 1-6 alkyl, NH 2 , NHC 1-6 alkyl, NHC(O)C 1-6 alkyl and NC 1-6 alkylC 1-6 alkyl; and 
 R 5  is selected from hydrogen, C 1-6 alkyl, C(O)C 1-6 alkyl, and (CH 2 ) n  phenyl, where n is 1, 2, 3, 4, 5 or 6 and phenyl may be unsubstituted or substituted by one or more substituents independently selected from C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, nitro, OC(O)C 1-6 alkyl, NH 2 , NHC 1-6 alkyl, NHC(O)C 1-6 alkyl and NC 1-6 alkylC 1-6 alkyl, 
 or a pharmaceutically acceptable salt, or solvate thereof, wherein blood glucose homeostasis in the subject is regulated by said effective amount of the sole anti-diabetic or anti-hyperglycemic agent. 
 
     
     
       2. A method for treating type II diabetes, gestational diabetes, impaired glucose tolerance, impaired fasting glucose or syndrome X in a subject in need thereof, consisting essentially of administering to said subject an effective amount of a compound of Formula (III) as a sole anti-diabetic or anti-hyperglycemic agent, 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from hydrogen, C 1-6 alkyl, C(O)C 1-6 alkyl and (CH 2 ) n  phenyl, where n is 1, 2, 3, 4, 5 or 6 and phenyl may be unsubstituted or optionally substituted by one or more substituents independently selected from C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, nitro, OC(O)C 1-6 alkyl, NH 2 , NHC 1-6 alkyl, NHC(O)C 1-6 alkyl and NC 1-6 alkylC 1-6 alkyl; and 
 R 5  is selected from hydrogen C 1-6 alkyl, C(O)C 1-6 alkyl, and (CH 2 ) n  phenyl, where n is 1, 2, 3, 4, 5 or 6 and phenyl may be unsubstituted or substituted by one or more substituents independently selected from C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, nitro, OC(O)C 1-6 alkyl, NH 2 , NHC 1-6 alkyl, NHC(O)C 1-6 alkyl and NC 1-6 alkylC 1-6 alkyl, 
 or a pharmaceutically acceptable salt, or solvate thereof, wherein type II diabetes, gestational diabetes, impaired glucose tolerance, impaired fasting glucose, or syndrome X is treated by said effective amount of the sole antidiabetic or anti-hyperglycemic agent. 
 
     
     
       3. The method of  claim 1  wherein said compound is methazolamide. 
     
     
       4. The method according to  claim 1  wherein the effective amount is from about 25 to about 100 mg per day. 
     
     
       5. The method according to  claim 1  wherein the effective amount is from about 10 to about 75 mg per day. 
     
     
       6. The method according to  claim 1  wherein the effective amount is from about 50 to about 75 mg per day. 
     
     
       7. The method according to  claim 1  wherein the effective amount is about 50 mg per day. 
     
     
       8. The method according to  claim 1  wherein the effective amount is about 75 mg per day. 
     
     
       9. The method of  claim 2  wherein said compound is methazolamide. 
     
     
       10. The method according to  claim 2  wherein the effective amount is from about 10 to about 100 mg per day. 
     
     
       11. The method according to  claim 2  wherein the effective amount is from about 25 to about 75 mg per day. 
     
     
       12. The method according to  claim 2  wherein the effective amount is from about 50 to about 75 mg per day. 
     
     
       13. The method according to  claim 2  wherein the effective amount is about 50 mg per day. 
     
     
       14. The method according to  claim 2  wherein the effective amount is about 75 mg per day. 
     
     
       15. A method of lowering elevated or maintaining normal blood glucose levels in a subject in need thereof, comprising administering to said subject a first effective amount of a first anti-diabetic or anti-hyperglycemic agent; and simultaneously or sequentially administering to the subject a second effective amount of a second anti-diabetic or anti-hyperglycemic agent,
 wherein the first anti-diabetic or anti-hyperglycemic agent is a compound of Formula (III), 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from hydrogen, C 1-6 alkyl, C(O)C 1-6 alkyl and (CH 2 ) n  phenyl, where n is 1, 2, 3, 4, 5 or 6 and phenyl may be unsubstituted or optionally substituted by one or more substituents independently selected from C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, nitro, OC(O)C 1-6 alkyl, NH 2 , NHC 1-6 alkyl, NHC(O)C 1-6 alkyl and NC 1-6 alkylC 1-6 alkyl; and 
 R 5  is selected from hydrogen, C 1-6 alkyl, C(O)C 1-6 alkyl, and (CH 2 ) n  phenyl, where n is 1, 2, 3, 4, 5 or 6 and phenyl may be unsubstituted or substituted by one or more substituents independently selected from C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, nitro, OC(O)C 1-6 alkyl, NH 2 , NHC 1-6 alkyl, NHC(O)C 1-6 alkyl and NC 1-6 alkylC 1-6 alkyl, or a pharmaceutically acceptable salt, or solvate thereof, 
 wherein the second anti-diabetic or anti-hyperglycemic agent is metformin, or a pharmaceutically acceptable salt thereof, 
 and wherein blood glucose homeostasis in the subject is regulated by said first and second effective amounts. 
 
     
     
       16. The method of  claim 15  wherein said compound of Formula (III) is methazolamide. 
     
     
       17. The method according to  claim 15  wherein the first effective amount of the compound of Formula (III) or pharmaceutically acceptable salt, or solvate thereof is from about 10 to about 100 mg per day. 
     
     
       18. The method according to  claim 15  wherein the first effective amount of the compound of Formula (III) or pharmaceutically acceptable salt, or solvate thereof is from about 25 to about 75 mg per day. 
     
     
       19. The method according to  claim 15  wherein the first effective amount of the compound of Formula (III) or pharmaceutically acceptable salt, or solvate thereof is from about 50 to about 75 mg per day. 
     
     
       20. The method according to  claim 15  wherein the first effective amount of the compound of Formula (III) or pharmaceutically acceptable salt, or solvate thereof is about 50 mg per day. 
     
     
       21. The method according to  claim 15  wherein the first effective amount of the compound of Formula (III) or pharmaceutically acceptable salt, or solvate thereof is about 75 mg per day. 
     
     
       22. The method according to  claim 15  wherein the metformin or a pharmaceutically acceptable salt thereof is administered at a dose equal to or less than 90% of that which would be required for metformin monotherapy. 
     
     
       23. A method for treating type II diabetes, gestational diabetes, impaired glucose tolerance, impaired fasting glucose or syndrome X in a subject in need thereof, comprising administering to said subject a first effective amount of a first anti-diabetic or anti-hyperglycemic agent; and simultaneously or sequentially administering to the subject a second effective amount of a second anti-diabetic or anti-hyperglycemic agent,
 wherein the first anti-diabetic or anti-hyperglycemic agent is a compound of Formula (III), 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from hydrogen, C 1-6 alkyl, C(O)C 1-6 alkyl and (CH 2 ) n  phenyl, where n is 1, 2, 3, 4, 5 or 6 and phenyl may be unsubstituted or optionally substituted by one or more substituents independently selected from C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, nitro, OC(O)C 1-6 alkyl, NH 2 , NHC 1-6 alkyl, NHC(O)C 1-6 alkyl and NC 1-6 alkylC 1-6 alkyl; and 
 R 5  is selected from hydrogen C 1-6 alkyl, C(O)C 1-6 alkyl, and (CH 2 ) n  phenyl, where n is 1, 2, 3, 4, 5 or 6 and phenyl may be unsubstituted or substituted by one or more substituents independently selected from C 1-6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, nitro, OC(O)C 1-6 alkyl, NH 2 , NHC 1-6 alkyl, NHC(O)C 1-6 alkyl and NC 1-6 alkylC 1-6 alkyl, or a pharmaceutically acceptable salt, or solvate thereof, 
 wherein the second anti-diabetic or anti-hyperglycemic agent is metformin, or a pharmaceutically acceptable salt thereof, 
 and wherein type II diabetes, gestational diabetes, impaired glucose tolerance, impaired fasting glucose or syndrome X in the subject is treated by said first and second effective amounts. 
 
     
     
       24. The method of  claim 23  wherein said compound of Formula (III) is methazolamide. 
     
     
       25. The method according to  claim 23  wherein the first effective amount of the compound of Formula (III) or pharmaceutically acceptable salt, or solvate thereof is from about 10 to about 100 mg per day. 
     
     
       26. The method according to  claim 23  wherein the first effective amount of the compound of Formula (III) or pharmaceutically acceptable salt, or solvate thereof is from about 25 to about 75 mg per day. 
     
     
       27. The method according to  claim 23  wherein the first effective amount of the compound of Formula (III) or pharmaceutically acceptable salt, or solvate thereof is from about 50 to about 75 mg per day. 
     
     
       28. The method according to  claim 23  wherein the first effective amount of the compound of Formula (III) or pharmaceutically acceptable salt, or solvate thereof is about 50 mg per day. 
     
     
       29. The method according to  claim 23  wherein the first effective amount of the compound of Formula (III) or pharmaceutically acceptable salt, or solvate thereof is about 75 mg per day. 
     
     
       30. The method according to  claim 23  wherein the metformin is administered at a dose equal to or less than 90% of that which would be required for metformin monotherapy.